Summary of Work: Neurodegenerative diseases pose an increasing challenge to public health as the population ages. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system. Its etiology is essentially unknown, but environmental neurotoxins may be involved. We have conducted a case-control study of ALS to investigate the role of cumulative lifetime exposure to lead and other neurotoxins, including mercury, solvents, and pesticides. Field work is complete; 110 ALS cases, 31 clinic controls, and 270 population controls were enrolled in the study. We assessed lead exposure in three ways: we measured bone lead using x-ray fluorescence, an innovative noninvasive technique; we measured blood lead; and we administered a structured in-person interview to gather information on potential occupational, residential, and lifestyle sources of exposure. Preliminary analyses showed that blood and bone lead were strongly correlated; both increased exponentially with age, but neither was associated with gender. Both were associated with occupational exposure to lead. After adjusting for age and gender, both blood and bone lead levels were higher in ALS cases, and cases were more likely to have occupational exposure to lead. Further analyses will be conducted to confirm these findings and explore the effects of other neurotoxins. In addition, dietary antioxidant intake will be evaluated as a protective factor and as a modifier of exposure-disease relationships. Polymorphisms in genes involved in xenobiotic metabolism or associated with ALS will also be studied, using PCR and RFLA, so that gene-environment interactions can be evaluated. Elucidation of the role of environmental neurotoxins in ALS may contribute to measures for prevention of this devastating disease and may in addition provide a paradigm for future studies of other neurodegenerative diseases.